Let curiosity lead you

It is an incredible honor to receive the Woman in Cell Biology Mid-Career Award for Excellence in Research. My lab works on cell–cell fusion, an indispensable process in the conception, development, and physiology of multicellular organisms. In this essay, I reflect on my curiosity-led journey, which uncovered some unexpected mechanisms underlying cell–cell fusion.

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TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

10.1101/711473 ◽

2019 ◽

Author(s):

Yang Zhang ◽

Trieu Le ◽

Ryan Grabau ◽

Zahra Mohseni ◽

Hoejeong Kim ◽

...

Keyword(s):

Cell Surface ◽

Cell Fusion ◽

Placental Development ◽

Cellular Mechanisms ◽

Developmental Defects ◽

Phospholipid Scramblase ◽

A Cell ◽

Fusion Signal ◽

Multicellular Organisms ◽

Cell Cell

AbstractCell-cell fusion or syncytialization is fundamental to the reproduction, development and homeostasis of multicellular organisms. In addition to various cell-type specific fusogenic proteins, cell surface externalization of phosphatidylserine (PS), a universal eat-me signal in apoptotic cells, has been observed in different cell-fusion events. Nevertheless, molecular underpinnings of PS externalization and cellular mechanisms of PS-facilitated cell-cell fusion are unclear. Here we report that TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), plays an indispensable role in placental trophoblast fusion by translocating PS to the cell surface independent of apoptosis. Consistent with its essential role in trophoblast fusion, the placentas from TMEM16F-deficient mice exhibit deficiency in syncytialization, placental developmental defects and perinatal lethality. Our findings thus identify a cell-cell fusion mechanism by which TMEM16F CaPLSase-dependent externalization of PS serves as a critical cell fusion signal to facilitate trophoblast syncytialization and placental development.

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TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

Science Advances ◽

10.1126/sciadv.aba0310 ◽

2020 ◽

Vol 6 (19) ◽

pp. eaba0310 ◽

Cited By ~ 1

Author(s):

Yang Zhang ◽

Trieu Le ◽

Ryan Grabau ◽

Zahra Mohseni ◽

Hoejeong Kim ◽

...

Keyword(s):

Cell Surface ◽

Cell Fusion ◽

Cell Types ◽

Placental Development ◽

Cellular Mechanisms ◽

Phospholipid Scramblase ◽

Perinatal Lethality ◽

Cell Type Specific ◽

Multicellular Organisms ◽

Cell Cell

Cell-cell fusion or syncytialization is fundamental to the reproduction, development, and homeostasis of multicellular organisms. In addition to various cell type–specific fusogenic proteins, cell surface externalization of phosphatidylserine (PS), a universal eat-me signal in apoptotic cells, has been observed in different cell fusion events. Nevertheless, the molecular underpinnings of PS externalization and cellular mechanisms of PS-facilitated cell-cell fusion are unclear. Here, we report that TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), plays an essential role in placental trophoblast fusion by translocating PS to cell surface independent of apoptosis. The placentas from the TMEM16F knockout mice exhibit deficiency in trophoblast syncytialization and placental development, which lead to perinatal lethality. We thus identified a new biological function of TMEM16F CaPLSase in trophoblast fusion and placental development. Our findings provide insight into understanding cell-cell fusion mechanism of other cell types and on mitigating pregnancy complications such as miscarriage, intrauterine growth restriction, and preeclampsia.

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Spectrin is a mechanoresponsive protein shaping the architecture of intercellular invasion

10.1101/154831 ◽

2017 ◽

Author(s):

Rui Duan ◽

Ji Hoon Kim ◽

Khurts Shilagardi ◽

Eric Schiffhauer ◽

Sungmin Son ◽

...

Keyword(s):

Cell Fusion ◽

Cell Biology ◽

Cell Shape ◽

Myosin Ii ◽

Mechanical Damage ◽

Fusion Partner ◽

Mechanical Tension ◽

Cellular Processes ◽

Skeletal Protein ◽

Cell Cell

Spectrin is a membrane skeletal protein best known for its structural role in maintaining cell shape and protecting cells from mechanical damage1-3. Here, we report that spectrin dynamically accumulates and dissolves at the fusogenic synapse, where an attacking fusion partner mechanically invades its receiving partner with actin-propelled protrusions to promote cell-cell fusion4-7. Using genetics, cell biology, biophysics and mathematical modeling, we demonstrate that unlike myosin II that responds to dilation deformation, spectrin exhibits a mechanosensitive accumulation in response to shear deformation, which is highly elevated at the fusogenic synapse. The accumulated spectrin forms an uneven network, which functions as a “sieve” to constrict the invasive fingerlike protrusions, thus putting the fusogenic synapse under high mechanical tension to promote cell membrane fusion. Taken together, our study has revealed a previously unrecognized function of spectrin as a dynamic mechanoresponsive protein that shapes the architecture of intercellular invasion. These findings have general implications for understanding spectrin function in other dynamic cellular processes beyond cell-cell fusion.

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SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

eLife ◽

10.7554/elife.65962 ◽

2021 ◽

Vol 10 ◽

Author(s):

David W Sanders ◽

Chanelle C Jumper ◽

Paul J Ackerman ◽

Dan Bracha ◽

Anita Donlic ◽

...

Keyword(s):

Membrane Fusion ◽

Cell Fusion ◽

Viral Entry ◽

Cell Biology ◽

Positive Outcomes ◽

Enveloped Viruses ◽

Multinucleated Cells ◽

Syncytia Formation ◽

New Strategies ◽

Cell Cell

Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with quantitative cell biology approaches, the screen reveals an essential role for biophysical aspects of the membrane, particularly cholesterol-rich regions, in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings potentially provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins, and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.

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Faculty Opinions recommendation of Structural basis of eukaryotic cell-cell fusion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718348654.793494093 ◽

2014 ◽

Author(s):

David Tareste

Keyword(s):

Cell Fusion ◽

Eukaryotic Cell ◽

Structural Basis ◽

Cell Cell

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Acquisition of Cell–Cell Fusion Activity by Amino Acid Substitutions in Spike Protein Determines the Infectivity of a Coronavirus in Cultured Cells

PLoS ONE ◽

10.1371/journal.pone.0006130 ◽

2009 ◽

Vol 4 (7) ◽

pp. e6130 ◽

Cited By ~ 22

Author(s):

Yoshiyuki Yamada ◽

Xiao Bo Liu ◽

Shou Guo Fang ◽

Felicia P. L. Tay ◽

Ding Xiang Liu

Keyword(s):

Amino Acid ◽

Cell Fusion ◽

Cultured Cells ◽

Spike Protein ◽

Amino Acid Substitutions ◽

Fusion Activity ◽

Cell Cell

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Desmosomal Molecules In and Out of Adhering Junctions: Normal and Diseased States of Epidermal, Cardiac and Mesenchymally Derived Cells

Dermatology Research and Practice ◽

10.1155/2010/139167 ◽

2010 ◽

Vol 2010 ◽

pp. 1-12 ◽

Cited By ~ 17

Author(s):

Sebastian Pieperhoff ◽

Mareike Barth ◽

Steffen Rickelt ◽

Werner W. Franke

Keyword(s):

Cell Biology ◽

Cell Types ◽

Cell Junctions ◽

Surface Molecules ◽

Transmembrane Glycoprotein ◽

Current Cell ◽

Plakophilin 2 ◽

Definition Of ◽

Adhering Junctions ◽

Cell Cell

Current cell biology textbooks mention only two kinds of cell-to-cell adhering junctions coated with the cytoplasmic plaques: the desmosomes (maculae adhaerentes), anchoring intermediate-sized filaments (IFs), and the actin microfilament-anchoring adherens junctions (AJs), including both punctate (puncta adhaerentia) and elongate (fasciae adhaerentes) structures. In addition, however, a series of other junction types has been identified and characterized which contain desmosomal molecules but do not fit the definition of desmosomes. Of these special cell-cell junctions containing desmosomal glycoproteins or proteins we review the composite junctions (areae compositae) connecting the cardiomyocytes of mature mammalian hearts and their importance in relation to human arrhythmogenic cardiomyopathies. We also emphasize the various plakophilin-2-positive plaques in AJs (coniunctiones adhaerentes) connecting proliferatively active mesenchymally-derived cells, including interstitial cells of the heart and several soft tissue tumor cell types. Moreover, desmoplakin has also been recognized as a constituent of the plaques of thecomplexus adhaerentesconnecting certain lymphatic endothelial cells. Finally, we emphasize the occurrence of the desmosomal transmembrane glycoprotein, desmoglein Dsg2, out of the context of any junction as dispersed cell surface molecules in certain types of melanoma cells and melanocytes. This broadening of our knowledge on the diversity of AJ structures indicates that it may still be too premature to close the textbook chapters on cell-cell junctions.

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